Mapping genes for schizophrenia in a founder population

描述（由申请人提供）：我们建议对南非阿非利卡人进行多管齐下的人类遗传分析，以确定家族性和非家族性（散发性）精神分裂症的遗传风险因素。我们在上一个资助周期内的工作为该疾病的散发性和家族性形式的遗传和生物学基础提供了三个重要的见解：首先，南非白人人群中至少10%的散发性精神分裂症病例可以由罕见的新生CNVs解释；第二，很大一部分家族性精神分裂症病例可以通过罕见的遗传CNVs来解释，这些CNVs富集于基因区域的缺失和重复；第三，部分患有精神分裂症的阿非利卡人家族在染色体13q34上携带一个或多个疾病风险基因。我们在该奖项最后一个资助期的工作代表了第一批基于家庭的研究之一，探索了CNVs如何促进精神分裂症已知遗传模式的重要问题，并指示了该项目下一个资助周期的研究方向。具体而言，我们计划(i)使用家族性和散发性精神分裂症的大队列以及对照队列进行新的高密度全基因组CNVs扫描；（ii）采用基于测序的方法，以确定受罕见CNVs影响的基因中潜在破坏性突变的总数或新生突变的数量是否明显高于对照组；（iii）基于两种互补的方法进行全面的努力，探索13q34精神分裂症易感位点的遗传结构，最终目标是确定一个或多个常见或罕见的变异，说明在该区域观察到的连锁信号。在独特的阿非利卡人群体中做这项研究的优势怎么强调都不为过。除了来自少数创始人的种族同质人口外，家庭结构，家谱研究的潜力以及几代人详细精神病学记录的可用性促进了以家庭为基础的精神分裂症研究以及零星和家族病例的高可信度区分。这个项目对揭示精神分裂症的遗传病因有着巨大的希望，特别是在新建立的技术允许有效筛选罕见突变的背景下。

DESCRIPTION (provided by applicant): We propose to undertake a multi-pronged human genetic analysis on the Afrikaners, a European origin founder population from South Africa, to identify genetic risk factors for both familial and non-familial (sporadic) forms of schizophrenia. Our work during the previous cycle of funding for this grant has provided three important insights in the genetic and biological basis of sporadic and familial forms of the disease: First, that at least 10 percent of sporadic cases of schizophrenia in the Afrikaner population can be accounted for by rare de novo CNVs; second, that a substantial portion of familial cases of schizophrenia can be accounted for by rare inherited CNVs enriched in deletions and duplications of genic regions; and third that a portion of Afrikaner families with schizophrenia carry one or more disease risk genes located at chromosome 13q34. Our work during the last funding period of this award represents one of the first family-based studies to explore the important question of how CNVs contribute to the known inheritance patterns of schizophrenia and dictates the research direction of this project for the next funding cycle. Specifically we plan to (i) undertake a new, high- density genome-wide scan for CNVs using large cohorts of familial and sporadic schizophrenia, as well as control cohorts; (ii) pursue sequencing based approaches to determine whether the total number of potentially damaging mutations or the number of de novo mutations in genes affected by rare CNVs is significantly higher in the cases versus controls; (iii) undertake a comprehensive effort based on two complementary approaches to probe the genetic architecture of the 13q34 schizophrenia susceptibility locus with a final goal to identify one or more common or rare variants accounting for the linkage signal observed in this region. The advantage of doing this research in the unique Afrikaner population cannot be overemphasized. In addition to being an ethnically homogeneous population derived from a small number of founders, the family structure, the potential for genealogical research and the availability of detailed psychiatric records over several generations facilitates family-based studies of schizophrenia and high-confidence distinction of sporadic and familial cases. This project holds tremendous promise to shed light into the genetic etiologies of schizophrenia, especially in the context of newly established technologies that allow efficient screens of rare mutations. PUBLIC HEALTH RELEVANCE: Our recent work has provided important insights into the genetic and biological basis of both familial and non- familial forms of schizophrenia, providing evidence that rare genomic copy number variants (CNVs) play an important role in the genetic risk of both forms of the disease. We propose to pursue further work to characterize the full spectrum of CNVs in schizophrenia and inform the genetic architecture of the disease more fully. We also propose to move beyond the CNV data and characterize in a comprehensive manner (using next generation sequencing approaches) genes located in identified disease risk loci, for additional RARE mutations that affect the function or expression of these genes.